DUSP4 promotes anti-tumor CD8⁺ T cell function and boosts CAR-T cell efficacy in mouse colorectal cancer

The activation and function of CD8⁺ T cells, which are central for anti-tumor immunity, are tightly regulated by extracellular and intracellular signaling pathways. Dual-specificity phosphatases (DUSP), including DUSP4, dephosphorylate serine/threonine and tyrosine residues of proteins to modulate cellular signaling. Here, we investigate the role of DUSP4 in cancer immunity. Patients with colorectal cancers (CRC) with lower DUSP4 expression across the CRC tissue exhibit shorter survival compared to those with higher DUSP4 expression. By contrast, in AOM/DSS-induced male mouse CRC models, global DUSP4 deficiency enhances tumorigenesis and compromises CD8⁺ T cell-mediated anti-tumor immunity. Mechanistically, DUSP4 knockout increases ERK2-mediated expression of the T cell activation regulator Klf2, thereby suppressing KLF2-mediated cytotoxic programs. In a CD19⁺ CRC xenograft mouse model, CRISPRa-mediated DUSP4 activation promotes anti-CD19 CAR-T cell proliferation and anti-tumor cytotoxicity. Thus, our data show that DUSP4 supports CD8⁺ T cell cytotoxic functions and suggest that DUSP4 may be a promising therapeutic target for enhancing anti-tumor immunity.